Molecular genetics of familial Alzheimer's disease

Defective genes play an important role in some, if not all cases of Alzheimer's disease (AD). Epidemiologic case control studies, family pedigree analysis, and recent twin studies clearly implicate inherited gene defects in development of the disease. In addition to defective genes, trisomy 21 also results in the neuropathology of AD and an increased risk of early dementia. The genetics of AD have been partially resolved. In some rare kindreds, AD is inherited by an autosomal dominant mechanism. In some of these rare families, mutations in the amyloid precursor protein (APP) gene on chromosome 21 are responsible for AD. APP mutations appear to account for approximately 5% of early-onset familial AD (FAD). Linkage analysis and a genomic scanning strategy have been used recently to localize an early-onset FAD locus to chromosome 14q24.3. This, as yet unidentified gene, accounts for FAD in most of the early-onset FAD kindreds which do not carry APP mutations. The chromosome 14 FAD locus is found in ethnically diverse populations including European Caucasians, Hispanics from Mexico, and in at least 1 Japanese family. However, the chromosome 14 locus is not responsible for FAD in the Volga German FAD families, a group of ethnically related kindreds with family age-of-onset means ranging from 50 to 65 years. Also, the chromosome 14 locus does not appear to be responsible for late-onset FAD. A locus on chromosome 19 appears to be a risk factor for AD in at least some late-onset FAD kindreds.(ABSTRACT TRUNCATED AT 250 WORDS)